Clinical efficacy, radiographic and safety findings through 5 years of subcutaneous golimumab treatment in patients with active
psoriatic arthritis: results from a long-term extension of a randomised, placebo-controlled trial, the GO-REVEAL study)

Results

Patient disposition and baseline characteristics

Four hundred and five patients were randomised and treated. Consent was obtained for the first patient on 12 December 2005;
the last patient completed wk268 (16 weeks after last study injection) on 13 January 2012. Patient disposition through wk24,6 wk527 and wk1048 have been reported. Among the 405 randomised patients, 126 (31%) discontinued study treatment through wk252 (see online supplementary
table S1). Radiographic images/scores were available for 304 patients at baseline and wk104 and for 267 patients at wk256.
For details of baseline patient and disease characteristics and concomitant medications, see online tables S1, S2, S3, and
supplemental material.

Efficacy results

Among randomised patients, wk256 response rates were 62.8–69.9%, 43.4–50.7% and 30.8–35.6% for American College of Rheumatology
≥20%/50%/70% improvement criteria (American College of Rheumatology, ACR20, ACR50 and ACR70, respectively; figure 1A). No consistent differences in ACR response by baseline methotrexate use were observed (figures 1B,C). Mean C-reactive-protein-based, 28-joint-count Disease Activity Scores (DAS28-CRP) at wk256 were 2.8–3.0 versus baseline
scores of 4.9–5.0 (table 1). DAS28-CRP responses and improvements in dactylitis and enthesitis scores are also summarised in table 1.

The proportions of patients achieving clinical improvement at week 256, defined by at least 20%, 50% and/or 70% improvement
in the American College of Rheumatology response criteria (ACR20, ACR50 and ACR70, respectively; A–C) or at least 50%, 75% and/or 90% improvement in the Psoriasis Area and Severity Index response criteria (PASI50, PASI75 and
PASI90, respectively) among randomised patients with baseline psoriasis involving ≥3% body surface area (D–F) among all patients (A, D) patients with methotrexate (MTX) use at baseline (B, E), and patients with no MTX use at baseline (C, F). Analyses were based on intent-to-treat analyses by randomised group, irrespective of treatment changes during the study.
The placebo group includes patients who were initially randomised to placebo and later early escaped/crossed over at week
16/24 to receive golimumab 50 mg, with the possibility to increase golimumab from 50 to 100 mg after the week-52 database
lock. The golimumab 50 mg group includes patients who were initially randomised to golimumab 50 mg and later early escaped
at week 16 or dose escalated after the week 52 database lock to receive golimumab 100 mg. All patients could decrease the
golimumab dose from 100 to 50 mg after the week-52 database lock.

At least 75% improvement in the Psoriasis Area and Severity Index (PASI75) (figure 1D) was achieved at wk256 in 60.8–72.2% of randomised patients with baseline psoriasis involving ≥3% body surface area. No
consistent differences in PASI responses by baseline methotrexate use were observed (figures 1E,F). Improvements in nail psoriasis severity were also evident (table 1).

The effect of golimumab dose escalation from 50 mg q4wks to 100 mg q4wks was evaluated for patients who had not achieved DAS28-CRP
<2.6 or PASI75 response before dose escalation. Increasing the golimumab dose yielded approximately 18% and 44% improvement
in DAS28-CRP and PASI scores, respectively (table 1).

For details of golimumab pharmacokinetic and antibody assessments, please see online supplementary materials. Antibodies-to-golimumab
developed in 6% (20/335), including 1.8% (3/165) and 10.0% (17/170), respectively, of patients receiving and not receiving
methotrexate at baseline.

Safety results

Per protocol, no patient received placebo beyond wk24. In general, no differences in the types of adverse events (AE) were
observed between golimumab doses (table 2). See online supplementary material for summaries of AEs reported after initiation of commercial drug, injection-site reactions,
and clinical laboratory findings.

Discussion

We previously reported golimumab (subcutaneous 50 and 100 mg q4wks) efficacy/safety in patients with active PsA. Golimumab-treated
patients displayed significant and/or clinically meaningful improvements in all aspects of PsA versus placebo.6,7 Despite no control arm, findings through wk104 of the LTE also supported golimumab's clinical and radiographic benefits.8 The current report extends the golimumab experience by 3 years, representing the longest available clinical trial data of
chronic anti-TNF treatment of PsA patients.

The GO-REVEAL trial retained more than two-thirds of randomised patients through 5 years, and although lacking a control after
wk24, data through 5 years provide further insight into golimumab efficacy and safety. At the last efficacy evaluation (wk256;
assessed with intent-to-treat (ITT) methodology), 63–70% and 43–51% of patients across randomised groups were ACR20 and ACR50
responders, respectively, and mean baseline DAS28-CRP scores decreased from 4.9–5.0 to <3.2 across treatment groups. Meaningful
improvements were also noted in physical function, enthesitis, dactylitis, and skin manifestations, including >60% of patients
achieving PASI75 improvement at wk256. Importantly, minimal changes in radiographic scores occurred from baseline to wk256
(mean change in total SHS ≤0.3), suggesting a long-term effect of golimumab on inhibiting radiographic progression.

No meaningful differences in efficacy outcomes were observed between the 50 mg and 100 mg doses of golimumab administered
q4wks; however, analyses were limited by allowed dose changes. Similarly, analyses of clinical response in arthritis and psoriasis
after dose escalation from 50 to 100 mg q4wks suggesting improved efficacy, especially in PASI scores, were limited by lack
of a control arm. Golimumab dose escalation occurred in approximately one-quarter of randomised patients and, given low discontinuation
rates due to lack of golimumab efficacy, likely reflects a treat-to-target therapeutic approach in patients with residual
disease activity.

Golimumab safety through 5 years was also consistent with those observed previously in this PsA patient population.6–8 Serious infections occurred in 15 patients; a limited number of patients had opportunistic infections, all while receiving
golimumab 100 mg. The incidence of antibodies to golimumab was low across the golimumab treatment groups and did not appear
to affect injection-site-reaction development. Consistent with earlier observations,6–8 fewer methotrexate-treated than untreated patients developed antibodies to golimumab. The incidences of all malignancies
excluding NMSC observed in GO-REVEAL did not differ from those expected in the general US population. No meaningful differences
in safety outcomes were observed between patients receiving golimumab 50 mg, 100 mg, or both doses, except opportunistic infections
(all reported for golimumab 100 mg).

Limitations of long-term data presented herein include the lack of a long-term control arm and golimumab dose changes, restricting
the ability to compare golimumab 50 mg with 100 mg. To compensate for such limitations, clinical efficacy data were evaluated
on an ITT basis (randomised patients with imputation for missing data). However, to avoid imputation of radiographic data,
radiographic analyses were based on patients who had available images at baseline/wk104/wk256, comprising ∼66% of randomised
patients. Although radiographic analyses including patients with available data are possibly biased by including responders
only, the alternative analyses employing all patients and imputation methodologies rely on assumptions made for patients with
missing data, also possibly leading to biased estimates of radiographic progression. Baseline disease characteristics were
similar between the radiographic patient subset and all randomised patients, indicating findings may be applicable to the
overall study population.

Despite discussed limitations, the safety and efficacy of golimumab 50 mg and 100 mg administered subcutaneously q4wks to
patients with active PsA were demonstrated through 5 years, as evidenced by sustained clinical and radiographic efficacy and
a safety profile consistent with other anti-TNF agents used for PsA.11

Footnotes

Handling editor Tore K Kvien

Contributors DG participated in the trial design and conduct and manuscript preparation. AK participated in the trial design and conduct
and manuscript preparation. GGK participated in the trial design and conduct and manuscript preparation. PM participated in
the trial design and conduct and manuscript preparation. IM participated in the trial design and conduct and manuscript preparation.
DvdH participated in the trial design and manuscript preparation. YZ, JL, JHL all contributed to data analysis and interpretation
and manuscript preparation, and NG and AB contributed to study design/ conduct, data interpretation, and manuscript preparation.

Ethics approval The study was conducted according to the Declaration of Helsinki and International Committee on Harmonisation good clinical
practices. The protocol was reviewed and approved by each site's governing institutional review board or ethics committee,
reflecting national requirements for study conduct approval. All patients provided written informed consent.

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works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

. How much improvement in functional status is considered important by patients with active psoriatic arthritis: applying the
outcome measures in rheumatoid arthritis clinical trials (OMERACT) group guidelines. Abstract presented at EULAR 2004. Ann Rheum Dis2004;63(Suppl 1):391–2.